Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo‐ and Racemic Praziquantel: Two Phase I Studies

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Abstract

Orally dispersible tablet ( ODT) formulations of levo praziquantel ( L‐PZQ) and racemic PZQ (rac‐PZQ) are being developed to treat schistosomiasis in preschool‐aged children. Two crossover studies ( N = 32 and 36, respectively) assessed the relative bioavailability of these ODTs vs. Cysticide in adults. Bioavailability for L‐ PZQ of ODT rac‐ PZQ and Cysticide at 40 mg/kg was comparable (L‐ PZQ area under the concentration‐time curve from zero to infinity ( AUC _0–∞) test/reference ratio (90% confidence interval (CI)): 96% (84–111%)), whereas relative bioavailability of ODT L‐ PZQ 20 mg/kg was ~40% that of Cysticide 40 mg/kg (test/reference: 40% (35–46%)). AUC _0‐∞ and peak plasma concentration (C _max) were highly variable in both studies. For both ODTs, L‐ PZQ AUC _0–∞ showed greater than dose‐proportional increase over the ranges tested and a significant food effect. Safety was comparable among formulations. The lower bioavailability of ODT L‐ PZQ, as well as the high variability and nondose‐proportionality of pharmacokinetic (PK) parameters, highlighted the need for a dedicated pediatric dose‐finding study for the selection of the most appropriate formulation and dose (L‐ PZQ ODT or rac‐ PZQ ODT).

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Unresolved issues in anthelmintic pharmacology for helminthiases of humans.

Timothy G. Geary, Katherine Woo, James McCarthy … (2010)

Helminth infections are an important constraint on the health and development of poor children and adults. Anthelmintic treatment programmes provide a safe and effective response, and increasing numbers of people are benefitting from these public health initiatives. Despite decades of clinical experience with anthelmintics for the treatment of human infections, relatively little is known about their clinical pharmacology. All of the drugs were developed initially in response to the considerable market for veterinary anthelmintics in high- and middle-income countries. In contrast, the greatest burden caused by these infections in humans is in resource-poor settings and as a result there has been insufficient commercial incentive to support studies on how these drugs work in humans, and how they should best be used in control programmes. The advent of mass drug administration programmes for the control of schistosomiasis, lymphatic filariasis, onchocerciasis and soil-transmitted helminthiases in humans increases the urgency to better understand and better monitor drug resistance, and to broaden the currently very narrow range of available anthelmintics. This provides fresh impetus for developing a comprehensive research platform designed to improve our understanding of these important drugs, in order to bring the scientific knowledge base supporting their use to a standard equivalent to that of drugs commonly used in developed countries. Furthermore, a better understanding of their clinical pharmacology will enable improved therapy and could contribute to the discovery of new products. Copyright 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

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Clinical Efficacy and Tolerability of Praziquantel for Intestinal and Urinary Schistosomiasis—A Meta-analysis of Comparative and Non-comparative Clinical Trials

Julien Zwang, Piero L. Olliaro (2014)

Introduction Some 779 million people are estimated to live in areas with varying levels of risk of contracting schistosomiasis [1]. The control and treatment of all forms of schistosomiasis is currently based on a single drug, praziquantel (PZQ). The World Health Organization (WHO) recommends that, in areas where the prevalence of infection is sufficiently high not to warrant individual diagnosis, a single dose of 40 mg/kg PZQ be distributed for preventive chemotherapy to either entire communities (through mass treatment) or school-aged children; or, where transmission is low, to be used to treat individuals with demonstrated infection [2]. Of note, while school-aged children are the main target of interventions, also younger children (preschool-aged) are now recognized as a vulnerable population [3], but data for this age group are limited. PZQ has been available for human use for over three decades, and distributed systematically through preventive chemotherapy from 2006. The cumulative number of treatments has been growing since. Some 34 million have received PZQ in 2010, and seven times more (235 millions) are projected for 2018 [4]; WHO has set target for 75% of the at-risk population to be under regular preventive chemotherapy [5]. With expanding use comes the need to monitor how PZQ performs in different areas, doses, over time and against different Schistosoma species. Two Cochrane systematic reviews have analyzed randomized controlled trials of anti-schistosomiasis treatments for S. haematobium [6] and S. mansoni [7]. A broader, aggregated data meta-analysis including non-comparative studies which did not qualify for the Cochrane reviews was undertaken here to help define more fully the efficacy and safety profile of PZQ across all species causing urinary and intestinal schistosomiasis, including mixed infections. The data generated from this meta-analysis was also intended to be used to help design future clinical investigations, in particular in young children treated with a new paediatric formulation currently developed by a public-private consortium [8]. Efficacy outcomes were measured for the different age-groups and doses and compared between various doses and to other drugs. Similarly, the tolerability profile of PZQ was assessed as incidence of adverse events (AE) and compared between various doses and to other drugs. Methods Data collection Published studies were identified by the Cochrane collaboration through electronic searches from January 1, 1990, up to November 2012 of MEDLINE, EMBASE, LILACS, the Cochrane Infectious Diseases Group's trials register and the Cochrane Central Register of Controlled Trials (CENTRAL) using the search term ‘praziquantel’ published in English, French or Portuguese. To qualify for inclusions, patients with a microscopic confirmation of schistosomiasis infection were to be on PZQ mono-therapy at any dosage and dosing regimen, using any formulation and brand; and could be either non-comparative or comparative (randomized controlled trial, quasi-randomized trials). In order to exclude the confounding effect of reinfections, efficacy analysis was restricted to the first 8 weeks post-treatment; hence, otherwise eligible studies with an endpoint beyond 8 weeks were not included in the final analysis. Statistical analysis The aggregated data (as reported in the publications) by species (S. haematobium, S. mansoni, S. japonicum, or mixed infections) were extracted from eligible studies of the 273 comparative and non-comparative clinical trials identified through the systematic review. Attrition bias refers to systematic differences between the number of patients at enrolment and at endpoint; it is measured as the number of patients not assessed out of the number of patients enrolled, and is considered high when greater than 10%. Cure rates (CR, defined as the conversion from a positive test pre-treatment to a negative test up to 8 weeks post-treatment) were calculated as provided in the articles. The confidence intervals for the CR were set at 95% (95%CI). The eggs reduction rate (ERR) was defined as the proportional reduction in the mean eggs per gram post-treatment vs. pre-treatment, calculated using geometric or arithmetic means and reported separately depending on how provided in the article. For both outcomes, the endpoint or time of assessment was divided in two groups: within a month (3 to 4 weeks) and between one and two months (5 to 8 weeks). The Spearman test was used to assess the bivariate correlations between the PZQ dose and CR or ERR in all treatment arms of comparative and non-comparative studies. Tolerability was assessed by calculating the incidence of adverse events (AE) defined as any sign or symptom occurring after the start of treatment (drug intake), irrespective of whether that sign or symptom was present at baseline or not, of its severity and drug-event relationship. The mean incidence was presented for the PZQ 40 mg/kg treatment groups excluding PZQ 40 mg/kg syrup, and Levo-PZQ 20 mg/kg. Most of the publications did not report the brand name and only two studies compared directly two different brands (Biltricide and Distocide) of PZQ. The 95%CI for the mean CR, ERR, AE were calculated using a bootstrap resampling method with a maximum of 1000 replicates [9]. For randomized controlled studies assessing the efficacy (CR) and tolerability (AE) of PZQ vs. other drugs, placebo, or comparing different PZQ dosing regimens, risk ratios with 95% confidence intervals (RR, 95%CI), meta-analysis with random effect on the study/site was used and pooled RR presented using the DerSimonian and Laird procedure for random effects models [10]. Heterogeneity was expressed as I2 [11]. CR and ERR were log-transformed in multivariate meta-regression to assess the PZQ dose-effect (continuous in mg/kg), along with age (continuous in year), endpoint (continuous in week) and date (continuous in year) with a random intercept for each study/site when the Lagrange multiplier (LM) test was significant to account for heterogeneity. Graphical displays of comparisons (PZQ vs. comparator groups) and heterogeneity for CR and ERR were illustrated using Forest plots [12]. Age groups were categorized as (i) preschool-aged children (<6 years old), (ii) school-aged children (6–19 years old), (iii) adults (20 years old or more), or (iv) all ages if age-specific data could not be extracted. The sample size (number of subjects by site), the endpoint (weeks), the intensity of infection at baseline (egg counts before treatment) were presented according to the Schistosoma species. Data were analyzed using Stata v11 (Stata Corp.). The PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement [13] was used as a guide in the reporting of this study. Results Study characteristics Of the 273 published studies identified by systematic search of the literature, 92 were PZQ treatment trials; of these, 37 studies had an endpoint for efficacy beyond 2 months and were excluded, leaving 55 studies (41 comparative, 14 non-comparative) with an endpoint within 8 weeks [14]–[68]. The first eligible study was published in 1979, and half of the studies were conducted by 1998. The studies enrolled a total of 19,499 subjects in 189 treatment arms. The median study size was 206 patients (range 43–1,540). Attrition was acceptable (9%, n = 17,718), leaving 91% of the subjects with efficacy outcomes at the time of the study endpoint; of these, 42% were assessed within 4 weeks in 30 studies, and 58% between 5–8 weeks in 25 studies. More subjects were assessed between 5–8 weeks for S. mansoni (65%) and S. japonicum (71%), while more were assessed on week 3–4 for S. haematobium in 56% of cases and mixed S. mansoni/haematobium infections in 71% of cases. PZQ contributed to 74% (n = 13,048) and comparator drug or placebo to 26% (n = 4,670) of all subjects with outcomes. Of the subjects treated with PZQ at doses comprised between 10 and 60 mg/kg, PZQ 40 mg/kg was the most frequent dose (56%, n = 9,990). CR was assessed in 17,017 subjects (of whom 12,273 (69%) treated with PZQ) and ERR in 13,007 subjects (77%, n = 10,023 on PZQ) (Figure 1). 10.1371/journal.pntd.0003286.g001 Figure 1 Flow chart of the number of studies and patients screened and eligible for the efficacy analyses of cure rate (CR) and egg reduction rates (ERR). Of the 41 comparative studies identified, 19 directly compared different doses and schedules of PZQ; 7 compared praziquantel with artesunate combined with praziquantel, sulfalene, sulfamethoxypyrazine/pyrimethamine, or mefloquine; 6 with artesunate alone; 3 with metrifonate; 1 with nitrifonate and 1 with metrifonate+nitrifonate; 6 with oxamniquine, 4 with oltipraz, 1 with albendazole, 1 with mefloquine, and 3 with PZQ in combination with artemether, albendazole, or metrifonate. Studies were conducted in 24 countries and 82 sites. The largest population was from the WHO AFRO region (13,251 subjects, 68%), followed by EMRO (Egypt, Sudan and Saudi Arabia, 23%). The largest groups were S. mansoni subjects enrolled in Egypt (n = 2,606, 13.4%), Kenya (11.9%), Sudan (9.0%) and Uganda (6.6%) (Table S1). The risk of attrition bias was low in 57%, high in 38% and not assessable in 5%. The risk was high in 45% (10/22) of the community-based studies and 31% (10/32) of the school-based studies. The assessment of bias and the main characteristics of these studies are summarized in Table 1 and Table S2. 10.1371/journal.pntd.0003286.t001 Table 1 Main characteristics of the studies included – S. haematobium (sh), S. japonicum (sj) and mixed infections S. haematobium-S. intercalatum (si). Publication Country End point Species Age range Total (n) PZQ referent Comparator Screening method dose n drug n sample(n)*day(n) Bornmann 2001 Gabon 2 sh 5–13 296 pzq40 89 other 207 1*1 Burchard 1984 Gabon 2 sh 5–14 138 pzq60 65 other 73 1*1 dup Davis 1981 Zambia 1 sh 7–17 151 pzq40 45 pzq20-60 106 1*3 de Clercq 2002 Senegal 2 sh 7–14 267 pzq40 133 other 134 1*2 Inyang-Etoh 2008 Nigeria 2 sh 4–20 174 pzq40 42 pzq40 + other 220 2*2 Keiser 2010 Ivory coast 1 sh 8–16 83 pzq40 26 other 57 2*1 King 2002 Kenya 2 sh 4–23 200 pzq40 101 pzq20 99 1*2 Latham 1990 Kenya 2 sh 7–15 48 pzq40 16 other 32 1*1 McMahon 1983 Tanzania 2 sh 1–60* 77 pzq30 30 other 47 1*2 McMahon 1979 Tanzania 1 sh 7–15 125 pzq40 65 pzq30 and placebo 60 3*3 Midzi 2008 Zimbabwe 2 sh 2–19 624 pzq40 624 1*3 N'goran 2003 Ivory coast 1 sh 5–15 354 pzq40 354 1*1 dup Olds 1999 Kenya 2 sh 6–19 380 pzq40 95 other 285 2*1 Oyideran 1981 Nigeria 1 sh 7–13 82 pzq40 40 pzq30 and placebo 42 1*3 Rey 1983 Niger 1 sh 15–19 188 pzq40 54 pzq30 and other 134 2*2 Sissoko 2009 Mali 1 sh 6–15 781 pzq40 389 other 392 1*1 dup Tchuente 2004 Cameroon 1 sh school 515 pzq40 515 1*2 Wilkins 1987 Gambia 1 sh 5–17 619 pzq40 143 pzq10-20 and other 476 1*1 Kern 1984 Gabon 2 sh + si 10–17 158 pzq60 77 other 81 1*2 Belizario 2007 Philippines 1 sj 10–19 203 pzq40 102 pzq60 and other 101 2*2 Hou 2008 China 2 sj 10–60 196 pzq60 55 other 141 2*1 tri Olds 1999 Phillipines, China 2 sj 5–16 793 pzq40 203 other and placebo 590 2*1 Olliaro 2011 Philippines 1 sj 7–12 200 pzq40 101 pzq60 99 1*2 dup Abu elyazed 1998 Egypt 2 sm 5–50 939 pzq40 551 pzq60 388 3*3 Barakat 2005 Egypt 1 sm 5–39 83 pzq40 38 other 45 1*2 Berhe 1999 Ethiopia 2 sm 5–17 541 pzq40 541 1*1 Botros 2005 Egypt 2 sm 7–73 271 Pzq40 165 other 106 1*3 daSilva 1986 Brazil 1 sm 14–60* 94 pzq55 48 other 46 3*1 Declerq 2000 Senegal 2 sm 6–61 156 pzq40 39 other 117 1*1 dup Declerq tmih 2000 Senegal 2 sm 1–50 110 pzq40 36 other 74 1*1 Degu 2002 Ethiopia 2 sm 10–14 148 pzq40 148 1*1 Friis 1988 Botswana 2 sm school 81 pzq40 81 1*1 dup Ghandour 1995 Saudi Arabia 1 sm 1–50 170 pzq40 170 na Gryseels 1987 Burundi 2 sm <20 and ≥20 1138 pzq40 272 pzq20-30 other 866 1*1 dup Guisse 1987 Senegal 1 sm 5–15 130 pzq40 67 pzq60 63 2*2 Homeida 1989 Sudan 2 sm 1–60* 806 pzq40 400 pzq40 brand2 406 1*1 Ismail 1994 Egypt 2 sm 6–18 463 pzq40 463 1*1 Kabatereine 2003 Uganda 2 sm 5–50* 482 pzq40 482 3*1 Kardaman 1983 Sudan 1 sm 5–60* 388 pzq40 388 2*1 Massoud 1984 Egypt 1 sm school 179 pzq40 59 pzq10-20 120 1*1 McMahon 1981 Tanzania 1 sm 1–60* 91 pzq40 49 pzq50 42 1*3 Metwally 1995 Egypt 1 sm 8–16 366 pzq40 149 pzq20 217 3*3 tri Mohamed 2009 Sudan 1 sm 8–17 92 pzq40 46 other 46 1*2 Navaratnam 2012 Uganda 1 sm 1–5 297 pzq40 149 syrup pzq40 148 3*1 Obonyo 2010 Kenya 1 sm 7–12 212 pzq40 106 other 106 1*1 dup Olds 1999 Kenya 2 sm 6–19 367 pzq40 82 other placebo 285 2*1 Olliaro 2011 Brazil 1 sm 10–19 190 pzq40 96 pzq60 94 1*2 dup Olliaro 2011 Mauritania 1 sm 10–19 185 pzq40 92 pzq60 93 1*2 dup Olliaro 2011 Tanzania 1 sm 10–19 244 pzq40 119 pzq60 125 1*2 dup Raso 2004 Ivory coast 2 sm 1–60* 161 pzq40 161 3*1 Simonsen 1990 Ethiopia 1 sm 5–14 206 pzq40 206 2*1 Sousa-Figueiredo 2012 Uganda 1 sm 1–7 369 pzq40 369 1*2 Stelma 1997 Senegal 2 sm 5–75 86 pzq40 44 other 42 2*2 Taddese 1988 Ethiopia 1 sm 17–52 194 pzq40 99 other 95 1*1 Teesdale 1984 Malawi 1 sm 9–15 69 pzq40 18 other 51 4*1 Thiongo'o 2002 Kenya 2 sm 5–17 1018 pzq40 526 pzq60 and other 492 1*3 dup Utzinger 2000 Ivory coast 1 sm 6–14 194 pzq60 194 1*4 El Tayeb 1988 Sudan 1 sm+sh 7–12 111 pzq40 54 other 57 1*2 Kardaman 1983 Sudan 1 sm+sh 5–60* 43 pzq40 43 2*1 Kardaman 1985 Sudan 2 sm+sh 7–11 211 pzq40 211 1*1 Taylor 1988 Zimbabwe 1 sm+sh 10–15 373 pzq40 77 pzq10-20-30 and placebo 296 3*1 The largest number of subjects with efficacy outcomes was for a S. mansoni infection (57.8%), followed by S. haematobium (29.3%), S. japonicum (7.9%) and mixed infections (5%). Most of the subjects were school-aged children (63.8%); preschool-aged children accounted for 2.9%, adults 4.7%, and subjects of all ages 28.6% (Table S3). Two studies including all age's subjects also specified age categories, including schoolchildren [36], [66]. Laboratory diagnosis To diagnose and quantify the infection, the trials on S. haematobium used the filtration method with up to two specimens in duplicates over three days except in one study using reagent strips, while trials on S. mansoni used the Kato-Katz technique with up to three specimens over three days in triplicates (Table S4). Egg counts were reported using different approaches (number of specimens and tests) for the different intestinal or urinary schistosomiasis species for 13,135 subjects. The mean egg count before treatment was 910 (95%CI 369–1642) and 251 (95%CI 201–307) eggs per gram of feces for S. mansoni, in studies using arithmetic or geometric means, respectively; 178 (95%CI 95–274) eggs per gram of feces for S. japonicum; and 125 (95%CI 60–196) and 137 (95%CI 70–226) eggs per mL of urine for S. haematobium, for arithmetic and geometric means, respectively. Efficacy In subjects treated with PZQ, the efficacy of PZQ in any species (n = 13,105) was measured in 508 (4%) preschool, 7,776 (59%) school-aged children, 428 (3%) adults, and 4,393 (34%) subjects of all ages. The number of treatment arms with different doses of PZQ varied greatly; the 40 mg/kg dose was by far the most common (66%, 77/117), followed by the 60 mg/kg dose (14%, 16/117). All doses were not tested on each and every species or age groups. The only dose administered in preschool-aged children was 40 mg/kg for S. mansoni; school-aged children received doses ranging 10–60 mg/kg (72% were on 40 mg/kg); adults received 20–40 mg/kg; studies on all-age subjects administered doses ranging 20–60 mg/kg (76% were on 30 mg/kg). Cure rates (CR) with PZQ Mean dose-specific CRs with 95%CIs by species are presented in Figure 2. CRs for any dose of PZQ appeared to be highest in S. japonicum infections (40 and 60 mg/kg); and were higher in S. haematobium, mixed S. haematobium/intercalatum and S. mansoni infections than in pure and mixed S. mansoni/haematobium infections. 10.1371/journal.pntd.0003286.g002 Figure 2 Forest plot of praziquantel (PZQ) cure rates with 95% CIs by species and dose (all age groups). sh, S. haematobium; si, S. intercalatum; sj, S. japonicum; sm, S. mansoni. The recommended dose of 40 mg/kg achieved CRs of 94.7% (95% CI 92.2–98.0) for S. japonicum, while it was 77.1% (95% CI 68.4–85.1) for S. haematobium, 76.7% (95% CI 71.9–81.2) for S. mansoni, and 63.5% (95% CI 48.2–77.0) for mixed S. haematobium and S. mansoni infections. Dose-effect analysis There was a significant relationship (Spearman test) between the CRs in subjects treated for S. mansoni and the PZQ dose: from 26.2% with PZQ 10 mg/kg to 84.6% with PZQ 60 mg/kg (r = 0.434, p = 0.001), as well as for mixed S. mansoni + S. haematobium infections (r = 0.764, p = 0.001) but not for S. haematobium (r = 0.019, p = 0.923) nor for S. japonicum (r = 0.396, p = 0.437). Endpoint analysis PZQ 40 mg/kg CRs assessed on week 3–4 were 82.7% (95%CI 70.3–92.9) and on week 5–8 were 69.9% (95%CI 58–78.7) for S. haematobium, and were 79.6% (95%CI 72.8–85.7) and 73.9% (95%CI 67.1–80.6) for S. mansoni, respectively. Although a direct comparison is not possible, 95%CIs overlap for both species. CR with PZQ 40 mg/kg vs. comparators The RR (95%CI) of CR between praziquantel 40 mg/kg and other PZQ regimens, placebo or other treatments are presented in Figure 3 for S. haematobium and Figures 4 and 5 for S. mansoni. 10.1371/journal.pntd.0003286.g003 Figure 3 Forest plot of relative risks of cure rates with 95%CIs, S. haematobium, PZQ 40 mg/kg vs. comparators. as, artesunate; ol, oltipraz; pzq, praziquantel; sp, sulfadoxine-pyrimethamine; met, metrifonate, mq, mefloquine; p, placebo; comp, comparator; unit next to the drug: dose in mg/kg; RR, risk ratio; I2 (Higgins' I squared) is calculated for pooled subgroups as = 100%*(Q - df)/Q, where Q is Cochran's heterogeneity statistic and df the degrees of freedom. 10.1371/journal.pntd.0003286.g004 Figure 4 Forest plot of risk ratios of cure rates with 95%CIs, S. mansoni, PZQ 40 mg/kg vs. other PZQ regimens. comp, comparator; ci, confidence interval; pzq, praziquantel; unit next to the drug: dose in mg/kg; RR, risk ratio; I2 (Higgins' I squared) is calculated for pooled subgroups as = 100%×(Q - df)/Q, where Q is Cochran's heterogeneity statistic and df the degrees of freedom. 10.1371/journal.pntd.0003286.g005 Figure 5 Forest plot of risk ratio of cure rates with 95%CIs, S. mansoni, PZQ 40 mg/kg vs. other regimens. as, artesunate; ox, oxamniquine; pzq, praziquantel; sp, sulfadoxine-pyrimethamine; mq, mefloquine; comp, comparator; ci, confidence interval; unit next to the drug: dose in mg/kg; RR, risk ratio; I2 (Higgins' I squared) is calculated for pooled subgroups as = 100%×(Q - df)/Q, where Q is Cochran's heterogeneity statistic and df the degrees of freedom. Using meta-analysis regression model with random effect on the sites, the CR for treating S. haematobium with praziquantel 40 mg/kg was higher than praziquantel 20 mg/kg (RR = 0.71, 95%CI 0.56–0.90, p = 0.004) and not different from praziquantel 30 mg/kg (p = 0.575); PZQ 40 mg/kg had higher CR than artesunate alone (RR = 0.55, 95%CI 0.36–0.83, p = 0.005) or in combinations, mefloquine alone, and metrifonate 10 mg/kg (RR = 0.15, 95%CI 0.04–0.58, p = 0.001). On S. mansoni, using similar methods, the CR of PZQ 40 mg/kg was higher than PZQ 20 mg/kg (RR = 0.65, 95%CI 0.59–0.72, p = 0.001), PZQ 30 mg/kg (RR = 0.89, 95%CI 0.75–0.95, p = 0.004), and not different from higher doses (50 mg/kg, p = 0.544; 60 mg/kg, p = 0.477); the CR for PZQ 40 mg/kg was significantly higher than artesunate and combinations, and myrrh (p = 0.001 for all comparisons); not different from oxamniquine 15, 20, 30 mg/kg; slightly lower than oxamniquine 40 mg/kg (RR = 1.09, 95%CI 1.01–0.18, p = 0.034), but not significantly different from oxamniquine 50 mg/kg (RR = 1.65, 95%CI 0.99–2.75, p = 0.056). On S. japonicum, using similar methods, the CR of PZQ 40 mg/kg was not different from PZQ 60 mg/kg (RR 1.02, 95%CI 0.97–1.07, p = 0.461), and higher than placebo (p = 0.001). On mixed S. haematobium and mansoni, the CR of PZQ 40 mg/kg was not significantly higher from lower PZQ dose (10 mg/kg: RR 0.15, p = 0.060; 20 mg/kg RR 0.63, p = 0.135; 30 mg/kg RR 0.86, p = 0.278). Eggs reduction rate (ERR) The ERR was measured for 13,007 subjects in 126 study/sites. ERR by species and PZQ dose from non-comparative and comparative trials are presented in Figure 6. 10.1371/journal.pntd.0003286.g006 Figure 6 PZQ egg reduction rates with 95% CIs by species and dose. ci, confidence interval; sh, S. haematobium; si, S. intercalatum; sj, S. japonicum; sm, S. mansoni. The mean ERR was over 90% in subjects of any age treated with PZQ doses greater than 10 mg/kg for S. haematobium and 87% or more for S. mansoni and 89% or more for S. mansoni/haematobium mixed infections (40 mg/kg); for S. japonicum, the ERR was ∼95% (40 and 60 mg/kg). There was no significant relationship (Spearman test) between the ERRs in subjects treated with any PZQ dose and species: S. mansoni (r = −0.126, p = 0.370), S. haematobium (r = 0.057, p = 0.786), as well as for S. japonicum (r = 0.236, p = 0.764). With PZQ 40 mg/kg, the ERR assessed was 94.6% (95%CI 89.9–98.0) on week 3–4 and 93.4% (95%CI 83.2–100) on week 5–8 for S. haematobium, for S. mansoni, the ERR was 87.4% (95%CI 82.7–91.5) and 72.0% (89.0%, 95%CI 83.7–94.2) respectively. More details on efficacy rates by age groups and dose are given in Table 2. 10.1371/journal.pntd.0003286.t002 Table 2 Cure rates (CR) and egg reduction rates (ERR) with 95% confidence intervals (95%CI) calculated by boot-strapping by age-group, species and praziquantel dose. Age group Species PZQ dose (mg/kg) Cure rate (CR) Egg reduction rate (ERR) CR Lower 95%CI Upper 95%CI N patients N treatment arms % assessed within 1 month Endpoint (median week) ERR Lower 95%CI Upper 95%CI N patients N treatment arms % assessed within 1 month Endpoint (median week) preschool sm 40 69.0% 56.4% 81.7% 414 2 100% 4 85.6% 82.2% 89.0% 414 2 100% 4 school-aged sh 10 87.0% 77.6% 97.6% 38 1 100% 4 20 98.1% 98.1% 98.1% 53 1 100% 4 98.4% 94.4% 99.9% 35 1 100% 4 30 71.0% 71.0% 71.0% 31 1 100% 4 92.6% 85.7% 99.6% 50 2 100% 4 40 76.6% 67.8% 85.2% 2490 18 56% 4 93.9% 89.1% 98.7% 1856 18 67% 4 60 82.5% 75.0% 90.0% 65 2 0% 6 sh + si 60 85.6% 76.0% 91.0% 77 3 0% 5 sj 40 94.7% 92.2% 98.0% 406 3 67% 3 95.0% 90.1% 99.9% 203 2 100% 3 60 97.5% 97.0% 98.0% 200 2 100% 3 95.4% 91.0% 99.9% 200 2 100% 3 sm 10 26.2% 26.2% 26.2% 61 1 100% 4 20 40.3% 24.9% 58.0% 376 4 75% 4 91.7% 86.7% 97.3% 100 1 0% 6 30 63.0% 63.0% 63.0% 187 1 0% 6 96.1% 93.5% 98.8% 187 1 0% 6 40 74.6% 68.3% 80.6% 2340 19 47% 5 89.1% 83.3% 94.2% 1856 18 43% 5 60 78.6% 67.8% 90.6% 667 5 60% 4 84.2% 73.5% 94.2% 667 5 60% 4 sm+sh 10 11.1% 4.2% 18.1% 73 2 100% 4 20 38.3% 36.7% 40.0% 61 2 100% 4 30 51.8% 31.4% 72.2% 72 2 100% 4 40 67.6% 52.4% 81.2% 342 5 60% 4 98.0% 87.1% 99.7% 54 1 100% 4 adult sh 30 97.4% 97.4% 97.4% 39 1 100% 4 40 94.4% 94.4% 94.4% 54 1 100% 4 sm 20 55.0% 55.0% 55.0% 53 1 0% 6 91.2% 84.7% 98.2% 53 1 0% 6 30 87.0% 87.0% 87.0% 102 1 0% 6 98.0% 95.5% 99.9% 102 1 0% 6 40 94.2% 91.0% 96.0% 180 3 67% 4 77.0% 63.0% 98.2% 180 3 67% 4 all ages sh 20 50.0% 50.0% 50.0% 99 1 0% 6 95.0% 90.9% 99.3% 99 1 0% 6 30 87.0% 87.0% 87.0% 30 1 0% 8 99.0% 95.5% 99.9% 30 1 0% 8 40 70.0% 70.0% 70.0% 101 1 0% 6 98.0% 95.3% 99.9% 101 1 0% 6 sj 60 96.4% 96.4% 96.4% 55 1 0% 6 sm 40 76.7% 67.7% 84.5% 3443 20 40% 5 85.5% 79.0% 91.4% 3443 20 40% 5 50 88.1% 88.1% 88.1% 42 1 100% 4 98.7% 95.4% 99.9% 42 1 100% 4 55 79.2% 79.2% 79.2% 48 1 100% 4 93.5% 87.0% 99.9% 48 1 100% 4 60 94.4% 92.5% 95.9% 575 3 67% 3 83.5% 68.7% 92.0% 575 3 67% 3 sm+sh 40 43.2% 43.2% 43.2% 37 1 100% 4 89.0% 80.6% 98.3% 37 1 100% 4 Legend: sh, S. haematobium; si, S. intercalatum; sj, S. japonicum; sm, S. mansoni. Brand analysis Both brands (Biltricide and Distocide) of PZQ 40 mg/kg were effective in reducing infection intensity (ERR was 99.5% for both groups)[31]; similarly, there was no difference in CR with either 40 mg/kg (pooled RR 0.99, 95%CI 0.96–1.03, p = 0.745)[31], [46], or 20 mg/kg (RR 0.85, 95%CI 0.54–1.31, p = 0.453)[31]. Tolerability Adverse events (AEs) Of the 273 published studies identified, signs and symptoms recorded within 48 hours of treatment were reported in 12,435 subjects enrolled in 40 studies: 25 studies from the efficacy analysis, contributing to 75% of the subjects assessed for tolerability (n = 9,151) and 15 additional studies, (n = 3,284) [69]–[83], meaning that 45% of the studies eligible for the efficacy meta-analysis reported on tolerability. Ninety-six (96) treatment arms were analyzed of which 64 were PZQ administered from 20 to 80 mg/kg. Most of the recorded AEs were gastro-intestinal, neurological and dermatological (Figure S1). On average the incidence of subjects experiencing at least one AE was 56.9% (95%CI 47.4–67.9) in twelve studies reporting this tolerability outcome and treating 2,027 subjects with PZQ 40 mg/kg (all brands). The incidence of specific AEs ranged from 2.3% for urticaria to 31.1% for abdominal pain (Table 3) – detailed below. 10.1371/journal.pntd.0003286.t003 Table 3 Adverse event incidence, praziquantel 40 mg/kg. Adverse event Number Incidence 95%CI Bootstrap Studies Patients (%) Lower bound Upper bound Any adverse event 13 2272 56.0 45.2 66.4 Abdominal pain 30 6212 31.1 22.0 39.0 Muscle pain 2 129 29.2 10.0 48.0 Joint pain 3 642 25.7 7.4 59.0 Dizziness 30 6328 13.9 9.1 19.0 Headache 27 5642 13.7 9.1 18.0 Diarrhea 27 5790 12.7 8.0 17.0 Fatigue 10 2279 11.6 5.4 18.0 nausea 22 5508 10.6 6.9 14.0 Itching/rash 15 2885 10.4 3.9 19.0 Weakness 5 882 10.0 3.7 17.0 Haematuria 3 727 9.6 0.0 23.0 Vertigo 3 304 8.7 3.8 14.0 Vomiting 26 5339 7.2 4.8 9.7 Legend. ci, confidence interval. AEs with PZQ 40 mg/k vs. comparators In comparative studies, and using meta-regression with random effect on the study/site, subjects treated with PZQ 40 mg/kg were at lower risk for any AE compared to PZQ 60 mg/kg (RR 0.73, 95%CI 0.59–0.90, p = 0.003), oxamniquine 25 mg/kg (RR 0.63, 95%CI 0.50–0.78, p = 0.001), metrifonate 3*10 mg/kg (RR 0.73, 95%CI 0.55–0.98, p = 0.036), while they were at higher risk compared to L-PZQ (RR 1.31, 95%CI 1.05–1.63, p = 0.018) and AS+SP (RR 2.26, 95%CI 1.50–3.41, p = 0.004); there was no difference between 40 mg/kg and PZQ doses (20 mg/kg, 30 mg/kg, 2*20 mg/kg), metrifonate 10 mg/kg, metrifonate 10 mg/kg + niridazole 25 mg/kg. When different brands were compared, Biltricide had more AEs than Distocide (RR 1.50, 95%CI 1.31–1.72, p = 0.001). The most frequent AEs are listed below by decreasing frequency in PZQ 40 mg/kg recipients. The incidence of abdominal pain was 31.8% (95%CI 24.4–39.9) in 6,495 subjects treated with PZQ 40 mg/kg in 30 treatment arms. Subject treated with PZQ 40 mg/kg were at higher risks for abdominal pain than PZQ 20 mg/kg (RR = 1.80, 95%CI 1.31–2.48, p = 0.001), metrifonate 10 mg/kg (RR = 1.50, 95%CI 1.21–1.86, p = 0.001), AS+SP (RR = 3.32, 95%CI 1.70–6.49, p = 0.001); while there was no significant difference between PZQ 40 mg/kg and PZQ at various dose (60 mg/kg, 30 mg/kg, 2*20 mg/kg, 2*25 mg/kg, 2*15 mg/kg, 2*35 mg/kg, 2*30 mg/kg, syrup 40 mg/kg), L-PZQ, mefloquine, AS, ASMQ, ASSP, metrifonate 30 mg/kg, nirifonate 150 mg/kg, metrifonate 10mg/kg + nirifonate 250 mg/kg. Divergent results were found when PZQ was compared to oxamniquine: in a study, subjects treated with PZQ 40 mg/kg were at lower risks (RR = 0.48, 95%CI 0.28–0.83, p = 0.001) than oxamniquine 25 mg/kg, while in another study they were at higher risks compared to oxamniquine at 15, 20, 30, 40 mg/kg (p<0.05). Subjects treated with Biltricide were at higher risk of abdominal pain than those treated with Distocide (RR = 2.34, 95%CI 1.74–3.14, p = 0.001). Muscle pain was reported in 29.2% (95%CI 10.0–48.0) of the 129 subjects receiving PZQ 40 mg/kg at two study/sites and not different from PZQ 2*30 mg/kg. No difference was detected either in two other studies comparing PZQ 55 mg/kg and oxamniquine 15 mg/kg. Joint pain was reported in 20.2% (95%CI 4.9–42.3) of the 1,097 subjects enrolled in four PZQ 40 mg/kg treatment arms. In comparative studies no difference was detected with metrifonate 10 mg/kg and oxamniquine 25 mg/kg; subjects treated with PZQ 40 mg/kg Distocide (3.7%) were at lower risk compared to PZQ 40 mg/kg Biltricide brand (7.4%, RR 0.50, 95%CI 0.28–0.89, p = 0.018). Headache was reported in 13.6% (95%CI 9.3–18.6) of the 5,958 PZQ 40 mg/kg recipients enrolled in 27 treatment arms. Subjects treated with PZQ 40 mg/kg were at lower risks than those on oxamniquine 20 mg/kg (RR 0.31, 95%CI 0.11–0.89, p = 0.020), oxamniquine 2*15 mg/kg (RR 9.00, 95%CI 1.18–68.42, p = 0.034) while no difference was detected in other studies vs. other dose of PZQ (from 20 up to 60 mg/kg, syrup 40 mg/kg or L-PZQ), artesunate and combinations, mefloquine, niridazole, or metrifonate. The incidence of diarrhea was 12.9% (95%CI 8.6–17.9) in 6,106 PZQ 40 mg/kg recipients enrolled in 27 treatment arms. Subjects treated with PZQ 40 mg/kg were at higher risks compared to PZQ 2*30 mg/kg (RR 14.10, 95%CI 1.92–103.68, p = 0.009) and oxamniquine 40 mg/kg (RR 0.03, 95%CI 0.01–0.19, p = 0.001). The risk was also higher with Biltricide than Distocide (RR 2.28, 95%CI 1.46–3.56, p = 0.001), while there was no difference between PZQ 2*20 mg/kg (6%) and PZQ 2*15mg/kg (1%) and PZQ 2*25 mg/kg (5%), or between PZQ 40 mg/kg tablet and syrup formulation, or between 40 mg/kg and other PZQ doses, artesunate combinations, metrifonate 10 mg/kg, mefloquine, and other oxamniquine doses. The incidence of dizziness was 11.9% (95%CI 7.9–16.2) in 5,522 PZQ 40 mg/kg recipients enrolled in 26 treatment arms. Subjects treated with PZQ 40 mg/kg were at lower risks than oxamniquine at any dose: 20 mg/kg (RR 0.31, 95%CI 0.21–0.48, p = 0.001), 25 mg/kg (RR 0.56, 95%CI 0.37–0.84, p = 0.005), 30 mg/kg (RR 0.21, 95%CI 0.14–0.32, p = 0.001), 40 mg/kg (RR 0.19, 95%CI 0.13–0.27, p = 0.001), while they were at higher risks compared to metrifonate 10 mg/kg (RR 1.60, 95%CI 1.06–2.43, p = 0.001); there was no difference between the different dose of PZQ treatment and syrup, L-PZQ, oltripaz 2*15 mg/kg, metrifonate 30 mg/kg, or niridazole 150 mg/kg. Nausea was reported in 10.6% (95%CI 6.8–14.9) in 5,824 PZQ 40 mg/kg subjects in 22 treatment arms. Subjects treated with PZQ 40 mg/kg were at higher risks for nausea compared to 2*30 mg/kg (RR 2.47, 95%CI 1.18–5.16, p = 0.001) and L-PZQ (RR 4.50, 95%CI 1.56–12.96, p = 0.001), while there was no difference between the different dose of PZQ (20, 25, 30, 2*15, 40, 2*25, 60, 2*35, 80 mg/kg), brands and formulations, artesunate and combinations, oltripaz 2*15 mg/kg, metrifonate 10, 30 mg/kg, oxamniquine (15, 20, 25, 30, 40 mg/kg), niridazole 150 mg/kg. The incidence of itching/rash was 9.8% (95%CI 3.8–18.2) in 3,340 PZQ 40 mg/kg recipients in 16 treatment arms. Splitting the dose (PZQ 2*20 mg/kg) decreased the risk of itching/rash (RR 0.03, 95%CI 1.01–0.52, p = 0.016) in one study; no difference was detected between PZQ brands, tablets vs. syrup, and between PZQ 40 mg/kg and 2*30, 2*25 mg/kg, metrifonate 10 and 30 mg/kg, oxamniquine at various doses (20, 25, 30, 50 mg/kg), artesunate combinations and niridazole 150 mg/kg. Fatigue was reported in 9.6% (95%CI 4.0–16.3) of the 2,595 PZQ 40 mg/kg recipients in 10 arms. Subjects treated with PZQ 40 mg/kg were at lower risks compared to oxamniquine 25 mg/kg (RR 0.17, 95%CI 0.05–0.58, p = 0.005) while there was no difference between PZQ 40 mg/kg compared to other doses of PZQ (2*15, 2*20, 2*25, 2*30 mg/kg), between PZQ brands, formulations, L-PZQ, oxamniquine 15 mg/kg, and metrifonate 10 mg/kg. The incidence of vomiting was 7.9% (95%CI 5.2–10.9) in 5,722 PZQ 40 mg/kg recipients enrolled in 27 treatment arms. Subjects treated with PZQ 40 mg/kg were at lower risks compared to 60 mg/kg (RR 0.44, 95%CI 0.26–0.72, p = 0.001) but at higher risk than PZQ 2*30 mg/kg (RR 2.51, 95%CI 1.26–4.97, p = 0.008); the risk was higher with Biltricide than Distocide (RR 3.53, 95%CI 1.88–6.63, p = 0.001). There was no difference between tablets and syrup, and between 40 mg/kg and other doses (20, 30, 2*20 mg/kg), L-PZQ, AS, ASSP, ASMQ, oxamniquine (15, 20, 25, 30 mg/kg) or metrifonate 3*10 mg/kg. Discussion This is, to our knowledge, the largest collection of PZQ treatment trials analyzed so far, with over 14,000 subjects receiving the drug at different doses. This population is much larger, but intrinsically less homogenous, than that of the two available Cochrane systematic reviews [6], [7]. This study complements the Cochrane systematic reviews by broadening the number of studies analyzed for efficacy as well as tolerability, and by allowing a side-by-side analysis of all Schistosoma species, including co-infections. The overall conclusions of these reviews are generally concordant, despite some minor differences, which are mostly related to the different criteria for including/excluding studies in either analyses. Provided basic methodological standards are guaranteed, relaxing eligibility criteria for meta-analysis to allow for both comparative and non-comparative trials can broaden the database and complement more classical meta-analysis of randomised controlled trials. This and the Cochrane meta-analyses point to the lack of methodological standardization of the studies analyzed: the number of subjects per study, age groups, species and PZQ doses varied greatly across the studies; different methodologies were used to detect eggs in excreta (number of samples taken; number of tests/sample) and to quantify efficacy (CR, ERR with arithmetic or geometric means). While studies extend over three decades and a range of countries, trends over time cannot be reliably derived. In 38% of the studies, patient attrition was greater than 10%, and this more in community-based (45%) than school-based studies (31%). Tolerability was unevenly assessed and reported. Statistical models have helped in deriving trends but cannot compensate for the lack of direct comparisons for dose and age effects. On the other hand, the large number of subjects allows generalizable conclusions, despite the inherent limitations of aggregated-data meta-analyses. The main findings of this meta-analysis are that: (1) Schistosoma species appear to respond differently to PZQ, with S. japonicum having the highest and mixed S. mansoni/haematobium infections the lowest response rates, both in terms of CR and ERR; (2) a dose-response trend was apparent for CR in S. mansoni and mixed S. mansoni/haematobium infections, but not S. haematobium or S. japonicum. No significant trend was apparent for ERR, the currently preferred outcome measure [4] for any of the Schistosoma species; (3) age did not appear to influence treatment outcomes. However, this should be interpreted with caution as the age groups enrolled were generally broad and details by age are generally not provided in the papers; furthermore, preschool-aged children are minimally represented in this population, received only 40 mg/kg, and only for S. mansoni; (4) a single praziquantel dose of 40 mg/kg appears a reasonable compromise for all species and ages, although in a proportion of cases efficacy may be lower than expected. The most studied groups were school-aged children (64% of all subjects), S. mansoni infections (58%) and the PZQ dose of 40 mg/kg (56%); 68% of subjects were in the WHO AFRO region (where the prevalence of the infection is highest). Preschool-aged children accounted for only ∼3% of the total population (meaning that information on younger children is limited, and that conclusions on age-related efficacy and safety may change when more data accumulate in this age group). It should also be noted that community-based studies (which generally enroll subjects of all ages) tend to have more drop-outs than school-based studies. Overall, the CR achieved with the WHO-recommended dose of 40 mg/kg was highest for S. japonicum (94.7%, 95%CI 92.2–98.0), followed by S. haematobium (77.1%, 95% CI 68.4–85.1) for S. haematobium, and S. mansoni (76.7%, 95% CI 71.9–81.2), and mixed S. haematobium and S. mansoni infections (63.5%, 95%CI 48.2–77.0). Recent WHO Standard Operating Procedures recommend that control programs should further investigate drug performance in populations where the ERR is found to be lower than 90% [4]. The average ERR obtained in school-aged children with the dose of 40 mg/kg was 95% for S. japonicum, 94% for S. haematobium, and 89% for S. mansoni. Since these values are derived from a collection of studies, the fact that the lower bound of the 95%CI (obtained by bootstrapping) was 90% for S. japonicum, 89% for S. haematobium, and 81% for S. mansoni means that a proportion of these sites might warrant further assessment. However, it is difficult to compare results obtained with a variety of diagnostic approaches and using different calculations (geometric or arithmetic means) to a ‘reference for drug efficacy’ that is based on a single examination of a single specimen and is expressed as geometric mean. Praziquantel efficacy may be influenced by a variety of factors, which could not be explored in detail using aggregated data and meta-analysis methods. Pre-treatment intensity of infection is one, which could not be fully accounted for by having it as covariate in the model, primarily because of the diversity of the diagnostic and calculation approaches used, and because it is reported as group mean (individual subject data meta-analyses are better suited to address this issue). The WHO-recommended dose of 40 mg/kg compared favorably to all other PZQ regimens and other treatments tested. The dose-response curve appears to be flat for S. haematobium and to plateau at 40 mg/kg for S. mansoni. This must be due to different species susceptibility, because this happens in spite of exposure to praziquantel increasing overproportionally with the dose (the first-pass-metabolism in the liver being dose-dependent with regard to capacity) [84]. Similar to the Cochrane review [7], oxamniquine at 40 and 50 mg/kg appears to be an effective, but less well tolerated, alternative limited however to S. mansoni, and no longer available in the WHO AFRO and EMRO regions. We provide an extensive report of safety findings. Tolerability was variably assessed in 12,435 subjects enrolled in 40 studies. Safety information was provided for 45% (25/55) of the studies included in the efficacy meta-analysis; we identified an additional 15 studies with safety information which were not included in the efficacy analysis. Reporting on safety was highly variable, and we cannot confidently conclude whether the absence of a given AE in a certain study means that it did not occur or it was not investigated. Lastly, the frequencies reported must be taken separately for each individual AE (they should not be accumulative), as some subjects might have experienced more than one AE. From comparative studies, risk seems not to change with the PZQ dose overall, although there are indications that higher doses may induce more events in some cases (e.g. 60 mg/kg had more of any AE and vomiting than 40 mg/kg; more abdominal pain with 40 mg/kg than 20 mg/kg), and that a split dose (20 mg/kg twice) may be better tolerated (in particular fewer cases of itching/rash). A direct comparison of two brands of praziquantel (Biltricide and Distocide) found the former to cause more AEs (abdominal pain, fever, diarrhea, headache, vomiting). The reason could be related to higher blood levels: when the pharmacokinetics of these two brands given at 40 mg/kg to healthy volunteers was compared, Biltricide peak concentration (Cmax) was 1.9 times higher (mean 1.281 vs. 0.685 µg/ml) and the area under the concentration curve (AUC) was 1.7 (mean 3550 vs. 2133 ng/h/ml) times higher than Distocide [47]. One limitation of the tolerability analysis relates to the diversity of the definitions of ‘events’ and methods to express incidence rates across studies. Therefore we opted for a permissive definition allowing for any sign or symptom occurring after treatment, acknowledging that this may indeed overestimate the real contribution of the treatment to the occurrence of events. Moreover information on signs or symptoms and their severity before treatment was only collected in a few studies so that it was not possible to detect which events were treatment-emergent. The adoption of more standardized methodologies in clinical studies would facilitate meta-analyses and strengthen the quality of evidence, as already pointed out for urinary schistosomiasis [85]; some of these questions can be answered more adequately only through an individual-subject data meta-analysis. Box 1 This is the largest collection of trials on praziquantel for treating urinary and intestinal schistosomiasis which has been meta-analysed for efficacy and safety Provided basic methodological standards are guaranteed, relaxing eligibility criteria for meta-analysis to allow for both comparative and non-comparative trials can broaden the database and complement more classical meta-analysis of randomised controlled trials Results support World Health Organization recommendations and are consistent with Cochrane systematic reviews Box 2 Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J (2006) Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis 6: 411–25. World Health Organization (2013) Assessing The Efficacy Of Anthelminthic Drugs Against Schistosomiasis And Soil-Transmitted Helminthiases. Available: http://apps.who.int/iris/bitstream/10665/79019/1/9789241564557_eng.pdf. Accessed 2/1/2014. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–88. Pocock SJ, Travison TG, Wruck LM (2008) How to interpret figures in reports of clinical trials. BMJ 336: 1166–9. Kramer CV, Zhang F, Sinclair D, Olliaro PL (2014) Drugs for treating urinary schistosomiasis. Cochrane Database Syst Rev 8: CD000053. Supporting Information Checklist S1 Prisma checklist. (PDF) Click here for additional data file. Figure S1 Flow chart of the number of studies and patients screened and eligible for the safety analysis. (BMP) Click here for additional data file. Table S1 Number of patients enrolled by country and species (all treatment arms). (PDF) Click here for additional data file. Table S2 Study design of the included publications: risks of bias and attrition. (PDF) Click here for additional data file. Table S3 Classing of studies by age groups based on reported age ranges. (PDF) Click here for additional data file. Table S4 Diagnostic approaches used in the studies (number of study/sites). (PDF) Click here for additional data file.

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Schistosomiasis in infants and preschool-aged children: Infection in a single Schistosoma haematobium and a mixed S. haematobium-S. mansoni foci of Niger.

Amadou Garba, Nouhou Barkiré, Ali Djibo … (2010)

The burden of schistosomiasis in infants and preschool-aged children and their mothers is poorly known. We carried out a cross-sectional epidemiological survey in two villages in Niger: Falmado is endemic for Schistosoma haematobium only, whereas a mixed S. haematobium-S. mansoni focus has been reported from Diambala. The survey examined 282 children (149 girls, 133 boys, average age: 2.6 years) and 224 mothers (average age: 30.1 years). For S. haematobium diagnosis, two urine samples obtained on consecutive days were subjected to the standard urine filtration method. Additionally, macro- and microhaematuria were determined. The diagnosis of S. mansoni was based on a single stool sample with duplicate Kato-Katz thick smears. In Diambala, a standardised, pre-tested questionnaire was administered to mothers, which recorded demographic data, treatment history with anthelminthic drugs, household sanitation and water supply, and bathing practices for their children. Prevalence of egg-patent S. haematobium infections among young children and their mothers was respectively 50.5% and 55.6%, in Falmado, and 60.5% and 72.2% in Diambala. The prevalence of S. mansoni infection in Diambala was 43.8% among children and 52.1% in mothers. Mixed egg-patent infections of S. haematobium and S. mansoni were revealed in 28.6% of the children and 37.3% of the mothers. Questionnaire data showed that 69.8% of the children were accompanied by their mothers to schistosomiasis transmission sites before they were 1 year of age, and that three-quarter of the mothers used water directly drawn from the irrigation canals to wash their children. To conclude, a substantive proportion of children below the age of 5 years had egg-patent schistosomiasis, inclusive of co-infection with S. haematobium and S. mansoni. In the context of schistosomiasis control, more attention should be paid on preschool-aged children and women of childbearing age, so that they can benefit from preventive chemotherapy, which in turn might increase effective coverage of those infected. 2010 Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Wilhelmina Maria Bagchus: wilhelmina.bagchus@merckgroup.com

Journal

Journal ID (nlm-ta): Clin Transl Sci

Journal ID (iso-abbrev): Clin Transl Sci

Journal ID (doi): 10.1111/(ISSN)1752-8062

Journal ID (publisher-id): CTS

Title: Clinical and Translational Science

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1752-8054

ISSN (Electronic): 1752-8062

Publication date (Electronic): 21 December 2018

Publication date (Print): January 2019

Volume: 12

Issue: 1 ( doiID: 10.1111/cts.v12.1 )

Pages: 66-76

Affiliations

[ ¹ ] Quantitative Pharmacology Merck Institute for Pharmacometrics (an affiliate of Merck KGaA, Darmstadt, Germany) Lausanne Switzerland

[ ² ] Merck KGaA Modderfontein South Africa

[ ³ ] Quantitative Pharmacology Merck KGaA Darmstadt Germany

[ ⁴ ] Global Health Institute Ares Trading S.A. Coinsins Switzerland

[ ⁵ ] Global Biostatistics Merck KGaA Darmstadt Germany

Author notes

[*] [* ] Correspondence:

Wilhelmina Maria Bagchus ( wilhelmina.bagchus@ 123456merckgroup.com )

Article

Publisher ID: CTS12601

DOI: 10.1111/cts.12601

PMC ID: 6342245

PubMed ID: 30536632

SO-VID: 6a416f79-2421-4f2c-be87-5d8a57a08fa8

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 14 September 2018

Date accepted : 24 October 2018

Page count

Figures: 4, Tables: 3, Pages: 11, Words: 7465

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Funded by: Bill and Melinda Gates Foundation

Award ID: OPP1063223T

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component-id cts12601

cover-date January 2019

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.5.6 mode:remove_FC converted:22.01.2019

Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo‐ and Racemic Praziquantel: Two Phase I Studies

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Unresolved issues in anthelmintic pharmacology for helminthiases of humans.

Clinical Efficacy and Tolerability of Praziquantel for Intestinal and Urinary Schistosomiasis—A Meta-analysis of Comparative and Non-comparative Clinical Trials

Schistosomiasis in infants and preschool-aged children: Infection in a single Schistosoma haematobium and a mixed S. haematobium-S. mansoni foci of Niger.

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